2-211671010-A-G

Variant names:

• chr2-211671010-A-G
• rs1851169
• NM_005235.3:c.1716+2154T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.1716+2154T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 151,992 control chromosomes in the GnomAD database, including 10,996 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10996 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 5 publications found

Genes affected

ERBB4 (HGNC:3432): (erb-b2 receptor tyrosine kinase 4) This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ERBB4 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 19

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.1716+2154T>C		intron	N/A	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.1716+2154T>C		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.1716+2154T>C		intron	N/A	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.1716+2154T>C		intron	N/A	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.1716+2154T>C		intron	N/A	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000484594.5	TSL:1	n.1768+2154T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55221 AN: 151874 Hom.: 11002 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.363 AC: 55218 AN: 151992 Hom.: 10996 Cov.: 32 AF XY: 0.357 AC XY: 26535 AN XY: 74280

African (AFR) AF: 0.251 AC: 10410 AN: 41468

American (AMR) AF: 0.360 AC: 5493 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1665 AN: 3468

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5176

South Asian (SAS) AF: 0.309 AC: 1486 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4007 AN: 10542

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.453 AC: 30774 AN: 67954

Other (OTH) AF: 0.386 AC: 813 AN: 2106

Alfa AF: 0.424 Hom.: 6849

Bravo AF: 0.356

Asia WGS AF: 0.140 AC: 491 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.3
DANN	Benign	0.86
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1851169; hg19: chr2-212535735;